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- PDB-9zez: Avian TRPM8 (Parus major) semi-swapped, calcium free, menthol bou... -

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Basic information

Entry
Database: PDB / ID: 9zez
TitleAvian TRPM8 (Parus major) semi-swapped, calcium free, menthol bound structure resolved in cell vesicles
ComponentsTransient receptor potential cation channel subfamily M member 8
KeywordsTRANSPORT PROTEIN / TRPM8 / transient receptor potential melastatin 8 / MEMBRANE PROTEIN / menthol
Function / homology
Function and homology information


ligand-gated calcium channel activity / plasma membrane
Similarity search - Function
TRPM, SLOG domain / : / : / SLOG in TRPM / TRPM2-like domain / Ion transport domain / Ion transport protein
Similarity search - Domain/homology
: / Transient receptor potential cation channel subfamily M member 8
Similarity search - Component
Biological speciesParus major (Great Tit)
MethodELECTRON MICROSCOPY / single particle reconstruction / cryo EM / Resolution: 3.41 Å
AuthorsChoi, K.Y. / Lin, X. / Cheng, Y. / Julius, D.
Funding support United States, 3items
OrganizationGrant numberCountry
Howard Hughes Medical Institute (HHMI) United States
National Institutes of Health/National Institute of Neurological Disorders and Stroke (NIH/NINDS)R35NS105038 United States
National Institutes of Health/National Institute of General Medical Sciences (NIH/NIGMS)R35GM140847 United States
CitationJournal: Nature / Year: 2026
Title: Structural energetics of cold sensitivity.
Authors: Kevin Y Choi / Xiaoxuan Lin / Yifan Cheng / David Julius /
Abstract: Thermosensitive transient receptor potential (TRP) ion channels enable somatosensory nerve fibres to detect changes in our thermal environment over a wide physiologic range. In mammals, the menthol ...Thermosensitive transient receptor potential (TRP) ion channels enable somatosensory nerve fibres to detect changes in our thermal environment over a wide physiologic range. In mammals, the menthol receptor, TRPM8, is activated by temperatures below approximately 26 °C and is essential for the perception of cold or chemical cooling agents. A fascinating, yet still unachieved goal is to elucidate mechanisms, both structural and thermodynamic, whereby TRPM8 or other thermosensitive channels are gated by changes in ambient temperature. Recent studies using cryogenic electron microscopy have attempted to address this challenging question but are limited by difficulties in visualizing temperature-evoked conformational sub-states or assessing the energetic landscape governing gating transitions. Here we close this gap by combining cryogenic electron microscopy with hydrogen-deuterium exchange mass spectrometry to elucidate a mechanism for cold-evoked activation of TRPM8. First, we visualize TRPM8 channels in cellular membranes, where bona fide menthol- and cold-evoked open states are captured. We also identify a new 'semi-swapped' architecture in which interdigitation of channel sub-units is rearranged substantially following repositioning of the S6 transmembrane helix and elements of the pore region. We then use hydrogen-deuterium exchange mass spectrometry to pinpoint the pore and TRP helices as the regions exhibiting the greatest stimulus-evoked energetic changes that drive channel gating. Specifically, cold-evoked stabilization of the outer pore region repositions the pore lining S6 transmembrane helix while enabling binding of a regulatory lipid to stabilize the open channel. Structural mechanisms associated with activation are validated by comparison of human TRPM8 with the menthol-sensitive but relatively cold-insensitive avian orthologue. We propose a free energy landscape and conformational pathway whereby cold or cooling agents activate this thermosensory receptor.
History
DepositionDec 1, 2025Deposition site: RCSB / Processing site: RCSB
Revision 1.0Apr 8, 2026Provider: repository / Type: Initial release
Revision 1.0Apr 8, 2026Data content type: EM metadata / Data content type: EM metadata / Provider: repository / Type: Initial release
Revision 1.0Apr 8, 2026Data content type: Additional map / Part number: 1 / Data content type: Additional map / Provider: repository / Type: Initial release
Revision 1.0Apr 8, 2026Data content type: Half map / Part number: 1 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 8, 2026Data content type: Half map / Part number: 2 / Data content type: Half map / Provider: repository / Type: Initial release
Revision 1.0Apr 8, 2026Data content type: Image / Data content type: Image / Provider: repository / Type: Initial release
Revision 1.0Apr 8, 2026Data content type: Primary map / Data content type: Primary map / Provider: repository / Type: Initial release

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Structure visualization

Structure viewerMolecule:
MolmilJmol/JSmol

Downloads & links

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Assembly

Deposited unit
A: Transient receptor potential cation channel subfamily M member 8
B: Transient receptor potential cation channel subfamily M member 8
C: Transient receptor potential cation channel subfamily M member 8
D: Transient receptor potential cation channel subfamily M member 8
hetero molecules


Theoretical massNumber of molelcules
Total (without water)509,4938
Polymers508,8684
Non-polymers6254
Water00
1


  • Idetical with deposited unit
  • defined by author
  • Evidence: electron microscopy, not applicable
TypeNameSymmetry operationNumber
identity operation1_5551

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Components

#1: Protein
Transient receptor potential cation channel subfamily M member 8


Mass: 127217.016 Da / Num. of mol.: 4
Source method: isolated from a genetically manipulated source
Source: (gene. exp.) Parus major (Great Tit) / Production host: Homo sapiens (human) / References: UniProt: A0A5S8WF66
#2: Chemical
ChemComp-XUQ / (1R,2S,5R)-5-methyl-2-(propan-2-yl)cyclohexan-1-ol / L-menthol


Mass: 156.265 Da / Num. of mol.: 4 / Source method: obtained synthetically / Formula: C10H20O / Feature type: SUBJECT OF INVESTIGATION
Has ligand of interestY
Has protein modificationN

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Experimental details

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Experiment

ExperimentMethod: ELECTRON MICROSCOPY
EM experimentAggregation state: PARTICLE / 3D reconstruction method: single particle reconstruction

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Sample preparation

ComponentName: Homotetrameric complex of Parus major TRPM8 determined in a cell-derived vesicles.
Type: COMPLEX / Entity ID: #1 / Source: RECOMBINANT
Molecular weightExperimental value: NO
Source (natural)Organism: Parus major (Great Tit)
Source (recombinant)Organism: Homo sapiens (human)
Buffer solutionpH: 7.4
Buffer component
IDConc.NameFormulaBuffer-ID
1300 mMpotassium chlorideKCl1
220 mMHEPESC8H18N2O4S1
30.5 mMFos-Choline-8, FluorinatedC13H17F13NO4P1
SpecimenEmbedding applied: NO / Shadowing applied: NO / Staining applied: NO / Vitrification applied: YES
Specimen supportGrid type: Quantifoil R1.2/1.3
VitrificationInstrument: FEI VITROBOT MARK IV / Cryogen name: ETHANE / Humidity: 100 % / Chamber temperature: 277.15 K

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Electron microscopy imaging

Experimental equipment
Model: Titan Krios / Image courtesy: FEI Company
MicroscopyModel: TFS KRIOS
Electron gunElectron source: FIELD EMISSION GUN / Accelerating voltage: 300 kV / Illumination mode: FLOOD BEAM
Electron lensMode: BRIGHT FIELD / Nominal magnification: 105000 X / Nominal defocus max: 2500 nm / Nominal defocus min: 1000 nm / Cs: 2.7 mm / C2 aperture diameter: 70 µm / Alignment procedure: COMA FREE
Specimen holderCryogen: NITROGEN / Specimen holder model: FEI TITAN KRIOS AUTOGRID HOLDER
Image recordingElectron dose: 47.7 e/Å2 / Film or detector model: GATAN K3 BIOQUANTUM (6k x 4k) / Num. of grids imaged: 2 / Num. of real images: 57257
EM imaging opticsEnergyfilter name: GIF Bioquantum / Energyfilter slit width: 10 eV

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Processing

EM software
IDNameVersionCategory
1cryoSPARC4particle selection
2SerialEMimage acquisition
4cryoSPARC4CTF correction
7Coot0.9.8.96model fitting
9cryoSPARC4initial Euler assignment
10cryoSPARC4final Euler assignment
12cryoSPARC3D reconstruction
13PHENIX1.21.2model refinement
CTF correctionType: PHASE FLIPPING AND AMPLITUDE CORRECTION
Particle selectionNum. of particles selected: 2898478
SymmetryPoint symmetry: C4 (4 fold cyclic)
3D reconstructionResolution: 3.41 Å / Resolution method: FSC 0.143 CUT-OFF / Num. of particles: 541958 / Symmetry type: POINT

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